Chronological age is a risk factor for SARS-CoV-2 infection and severe COVID-19. Previous findings indicate that epigenetic age could be altered in viral infection. However, the epigenetic aging in ...COVID-19 has not been well studied. In this study, DNA methylation of the blood samples from 232 healthy individuals and 413 COVID-19 patients is profiled using EPIC methylation array. Epigenetic ages of each individual are determined by applying epigenetic clocks and telomere length estimator to the methylation profile of the individual. Epigenetic age acceleration is calculated and compared between groups. We observe strong correlations between the epigenetic clocks and individual's chronological age (r > 0.8, p < 0.0001). We also find the increasing acceleration of epigenetic aging and telomere attrition in the sequential blood samples from healthy individuals and infected patients developing non-severe and severe COVID-19. In addition, the longitudinal DNA methylation profiling analysis find that the accumulation of epigenetic aging from COVID-19 syndrome could be partly reversed at late clinic phases in some patients. In conclusion, accelerated epigenetic aging is associated with the risk of SARS-CoV-2 infection and developing severe COVID-19. In addition, the accumulation of epigenetic aging from COVID-19 may contribute to the post-COVID-19 syndrome among survivors.
In recent years, research on sphingolipids, particularly ceramides, has attracted increased attention, revealing the important roles and many functions of these molecules in several human ...neurological disorders. The nervous system is enriched with important classes of sphingolipids, e.g., ceramide and its derivatives, which compose the major portion of this group, particularly in the form of myelin. Ceramides have also emerged as important nodes for lipid signalling, both inside the cell and between cells. Until recently, knowledge about ceramides in the nervous system was limited, but currently, multiple links between ceramide signalling and neurological diseases have been reported. Alterations in the regulation of ceramide pathobiology have been shown to influence the risk of developing neurometabolic diseases. Thus, these molecules are critically important in the maintenance and development of the nervous system and are culprits or major contributors to the development of brain disorders, either inherited or multifactorial. In the present review, we highlight the critical role of ceramide signalling in several different neurological disorders as well as the effects of their perturbations and discuss how this emerging class of bioactive sphingolipids has attracted interest in the field of neurological diseases.
Deregulation of purine metabolism in Alzheimer's disease Ansoleaga, Belén; Jové, Mariona; Schlüter, Agatha ...
Neurobiology of aging,
2015, January 2015, 2015-Jan, 2015-01-00, 20150101, 2015-01-01, Letnik:
36, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Abstract The neuroprotective role of adenosine and the deregulation of adenosine receptors in Alzheimer's disease (AD) have been extensively studied in recent years. However, little is known about ...the involvement of purine metabolism in AD. We started by analyzing gene expression in the entorhinal cortex of human controls and AD cases with whole-transcript expression arrays. Once we identified deregulation of the cluster purine metabolism, messenger RNA expression levels of 23 purine metabolism genes were analyzed with qRT-PCR in the entorhinal cortex, frontal cortex area 8, and precuneus at stages I-II, III-IV, and V-VI of Braak and Braak and controls. APRT, DGUOK, POLR3B, ENTPD3, AK5, NME1, NME3, NME5, NME7, and ENTPD2 messenger RNAs were deregulated, with regional variations, in AD cases when compared with controls. In addition, liquid chromatography mass spectrometry based metabolomics in the entorhinal cortex identified altered levels of dGMP, glycine, xanthosine, inosine diphosphate, guanine, and deoxyguanosine, all implicated in this pathway. Our results indicate stage- and region-dependent deregulation of purine metabolism in AD.
Background
In a recent study, autoantibodies neutralizing type I interferons (IFNs) were present in at least 10% of cases of critical COVID-19 pneumonia. These autoantibodies neutralized most type I ...IFNs but rarely IFN-beta.
Objectives
We aimed to define the prevalence of autoantibodies neutralizing type I IFN in a cohort of patients with severe COVID-19 pneumonia treated with IFN-beta-1b during hospitalization and to analyze their impact on various clinical variables and outcomes.
Methods
We analyzed stored serum/plasma samples and clinical data of COVID-19 patients treated subcutaneously with IFN-beta-1b from March to May 2020, at the Infanta Leonor University Hospital in Madrid, Spain.
Results
The cohort comprised 47 COVID-19 patients with severe pneumonia, 16 of whom (34%) had a critical progression requiring ICU admission. The median age was 71 years, with 28 men (58.6%). Type I IFN-alpha- and omega-neutralizing autoantibodies were found in 5 of 47 patients with severe pneumonia or critical disease (10.6%), while they were not found in any of the 118 asymptomatic controls (
p
= 0.0016). The autoantibodies did not neutralize IFN-beta. No demographic, comorbidity, or clinical differences were seen between individuals with or without autoantibodies. We found a significant correlation between the presence of neutralizing autoantibodies and higher C-reactive protein levels (
p
= 5.10e
−03
) and lower lymphocyte counts (
p
= 1.80e
−02
). No significant association with response to IFN-beta-1b therapy (
p
= 0.34) was found. Survival analysis suggested that neutralizing autoantibodies may increase the risk of death (4/5, 80% vs 12/42, 28.5%).
Conclusion
Autoantibodies neutralizing type I IFN underlie severe/critical COVID-19 stages in at least 10% of cases, correlate with increased C-RP and lower lymphocyte counts, and confer a trend towards increased risk of death. Subcutaneous IFN-beta treatment of hospitalized patients did not seem to improve clinical outcome. Studies of earlier, ambulatory IFN-beta treatment are warranted.
X‐adrenoleukodystrophy (X‐ALD) is a metabolic, peroxisomal disease affecting the nervous system, adrenal cortex and testis resulting from inactivating mutations in ABCD1 gene which encodes a ...peroxisomal membrane half‐adenosine triphosphate (ATP)‐binding cassette transporter, ABCD1 (or ALDP), whose defect is associated with impaired peroxisomal β‐oxidation and accumulation of saturated very long‐chain fatty acids (VLCFA) in tissues and body fluids. Several phenotypes are recognized in male patients including cerebral ALD in childhood, adolescence or adulthood, adrenomyeloneuropathy (AMN), Addison's disease and, eventually, gonadal insufficiency. Female carriers might present with mild to severe myeloneuropathy that resembles AMN. There is a lack of phenotype–genotype correlations, as the same ABCD1 gene mutation may be associated with different phenotypes in the same family, suggesting that genetic, epigenetic, environmental and stochastic factors are probably contributory to the development and course of the disease. Degenerative changes, like those seen in pure AMN without cerebral demyelination, are characterized by loss of axons and secondary myelin in the long tracts of the spinal cord, possibly related to the impaired lipid metabolism of VLCFAs and the associated alterations (ie, oxidative damage). Similar lesions are encountered following inactivation of ABCD1 in mice (ABCD1‐). A different and more aggressive phenotype is secondary to cerebral demyelination, very often accompanied by inflammatory changes in the white matter of the brain and associated with activation of T lymphocytes, CD1 presentation and increased levels of cytokines, γ‐interferon, interleukin (IL)‐1α, IL‐2 and IL‐6, Granulocyte macrophage colony‐stimulating factor (GM‐CSF), tumor necrosis factor‐α, chemokines and chemokine receptors.
We previously demonstrated that the deletion of the poly(ADP-ribose)polymerase (Parp)-1 gene in mice enhances oxidative metabolism, thereby protecting against diet-induced obesity. However, the ...therapeutic use of PARP inhibitors to enhance mitochondrial function remains to be explored. Here, we show tight negative correlation between Parp-1 expression and energy expenditure in heterogeneous mouse populations, indicating that variations in PARP-1 activity have an impact on metabolic homeostasis. Notably, these genetic correlations can be translated into pharmacological applications. Long-term treatment with PARP inhibitors enhances fitness in mice by increasing the abundance of mitochondrial respiratory complexes and boosting mitochondrial respiratory capacity. Furthermore, PARP inhibitors reverse mitochondrial defects in primary myotubes of obese humans and attenuate genetic defects of mitochondrial metabolism in human fibroblasts and C. elegans. Overall, our work validates in worm, mouse, and human models that PARP inhibition may be used to treat both genetic and acquired muscle dysfunction linked to defective mitochondrial function.
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•Inhibition of poly(ADP-ribose) polymerases (PARPs) enhances endurance performance•Inhibition of PARPs improves mitochondrial function in skeletal muscle•Parp-1 correlates with energy expenditure in heterogeneous mouse populations•Genetic and acquired mitochondrial defects can be rescued by PARP inhibition
Pirinen et al. show that long-term pharmacological poly(ADP-ribose) polymerase (PARP) inhibition enhances muscle mitochondrial function and fitness in mice. PARP inhibitors also improve genetic or acquired mitochondrial dysfunction in worms and human cells, highlighting their therapeutic use for muscle dysfunction associated with defective mitochondrial function.
The endoplasmic reticulum enzyme fatty acid 2-hydroxylase (FA2H) plays a major role in the formation of 2-hydroxy glycosphingolipids, main components of myelin. FA2H deficiency in mice leads to ...severe central demyelination and axon loss. In humans it has been associated with phenotypes from the neurodegeneration with brain iron accumulation (fatty acid hydroxylase-associated neurodegeneration, FAHN), hereditary spastic paraplegia (HSP type SPG35) and leukodystrophy (leukodystrophy with spasticity and dystonia) spectrum. We performed an in-depth clinical and retrospective neurophysiological and imaging study in a cohort of 19 cases with biallelic FA2H mutations. FAHN/SPG35 manifests with early childhood onset predominantly lower limb spastic tetraparesis and truncal instability, dysarthria, dysphagia, cerebellar ataxia, and cognitive deficits, often accompanied by exotropia and movement disorders. The disease is rapidly progressive with loss of ambulation after a median of 7 years after disease onset and demonstrates little interindividual variability. The hair of FAHN/SPG35 patients shows a bristle-like appearance; scanning electron microscopy of patient hair shafts reveals deformities (longitudinal grooves) as well as plaque-like adhesions to the hair, likely caused by an abnormal sebum composition also described in a mouse model of FA2H deficiency. Characteristic imaging features of FAHN/SPG35 can be summarized by the 'WHAT' acronym: white matter changes, hypointensity of the globus pallidus, ponto-cerebellar atrophy, and thin corpus callosum. At least three of four imaging features are present in 85% of FA2H mutation carriers. Here, we report the first systematic, large cohort study in FAHN/SPG35 and determine the phenotypic spectrum, define the disease course and identify clinical and imaging biomarkers.
Patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for the coronavirus disease 2019 (COVID-19), exhibit a wide spectrum of disease behaviour. Since ...DNA methylation has been implicated in the regulation of viral infections and the immune system, we performed an epigenome-wide association study (EWAS) to identify candidate loci regulated by this epigenetic mark that could be involved in the onset of COVID-19 in patients without comorbidities.
Peripheral blood samples were obtained from 407 confirmed COVID-19 patients ≤ 61 years of age and without comorbidities, 194 (47.7%) of whom had mild symptomatology that did not involve hospitalization and 213 (52.3%) had a severe clinical course that required respiratory support. The set of cases was divided into discovery (n = 207) and validation (n = 200) cohorts, balanced for age and sex of individuals. We analysed the DNA methylation status of 850,000 CpG sites in these patients.
The DNA methylation status of 44 CpG sites was associated with the clinical severity of COVID-19. Of these loci, 23 (52.3%) were located in 20 annotated coding genes. These genes, such as the inflammasome component Absent in Melanoma 2 (AIM2) and the Major Histocompatibility Complex, class I C (HLA-C) candidates, were mainly involved in the response of interferon to viral infection. We used the EWAS-identified sites to establish a DNA methylation signature (EPICOVID) that is associated with the severity of the disease.
We identified DNA methylation sites as epigenetic susceptibility loci for respiratory failure in COVID-19 patients. These candidate biomarkers, combined with other clinical, cellular and genetic factors, could be useful in the clinical stratification and management of patients infected with the SARS-CoV-2.
The Unstoppable campaign of the Josep Carreras Leukaemia Foundation, the Cellex Foundation and the CERCA Programme/Generalitat de Catalunya.
Sphingolipids function as membrane constituents and signaling molecules, with crucial roles in human diseases, from neurodevelopmental disorders to cancer, best exemplified in the inborn errors of ...sphingolipid metabolism in lysosomes. The dihydroceramide desaturase Δ4-dihydroceramide desaturase 1 (DEGS1) acts in the last step of a sector of the sphingolipid pathway, de novo ceramide biosynthesis. Defects in DEGS1 cause the recently described hypomyelinating leukodystrophy-18 (HLD18) (OMIM #618404). Here, we reveal that DEGS1 is a mitochondria-associated endoplasmic reticulum membrane-resident (MAM-resident) enzyme, refining previous reports locating DEGS1 at the endoplasmic reticulum only. Using patient fibroblasts, multiomics, and enzymatic assays, we show that DEGS1 deficiency disrupts the main core functions of the MAM: (a) mitochondrial dynamics, with a hyperfused mitochondrial network associated with decreased activation of dynamin-related protein 1; (b) cholesterol metabolism, with impaired sterol O-acyltransferase activity and decreased cholesteryl esters; (c) phospholipid metabolism, with increased phosphatidic acid and phosphatidylserine and decreased phosphatidylethanolamine; and (d) biogenesis of lipid droplets, with increased size and numbers. Moreover, we detected increased mitochondrial superoxide species production in fibroblasts and mitochondrial respiration impairment in patient muscle biopsy tissues. Our findings shed light on the pathophysiology of HLD18 and broaden our understanding of the role of sphingolipid metabolism in MAM function.
The nuclear factor erythroid 2‐like 2 (NRF2) is the master regulator of endogenous antioxidant responses. Oxidative damage is a shared and early‐appearing feature in X‐linked adrenoleukodystrophy ...(X‐ALD) patients and the mouse model (Abcd1 null mouse). This rare neurometabolic disease is caused by the loss of function of the peroxisomal transporter ABCD1, leading to an accumulation of very long‐chain fatty acids and the induction of reactive oxygen species of mitochondrial origin. Here, we identify an impaired NRF2 response caused by aberrant activity of GSK‐3β. We find that GSK‐3β inhibitors can significantly reactivate the blunted NRF2 response in patients’ fibroblasts. In the mouse models (Abcd1− and Abcd1−/Abcd2−/− mice), oral administration of dimethyl fumarate (DMF/BG12/Tecfidera), an NRF2 activator in use for multiple sclerosis, normalized (i) mitochondrial depletion, (ii) bioenergetic failure, (iii) oxidative damage, and (iv) inflammation, highlighting an intricate cross‐talk governing energetic and redox homeostasis in X‐ALD. Importantly, DMF halted axonal degeneration and locomotor disability suggesting that therapies activating NRF2 hold therapeutic potential for X‐ALD and other axonopathies with impaired GSK‐3β/NRF2 axis.
Synopsis
This study reports an aberrant, chronic inhibition of the endogenous antioxidant response driven by NRF2 in adrenoleukodystrophy. Reactivating this pathway in the mouse model with dimethyl fumarate unveils a promising therapeutic option.
NRF2‐mediated antioxidant response is impaired in X‐linked adrenoleukodystrophy (X‐ALD) mouse spinal cord and human fibroblasts.
Aberrant GSK‐3β activity is responsible for the NRF2 blunted response against oxidative stress in X‐ALD fibroblasts.
Molecular defects present in the X‐ALD mouse model are rescued after oral treatment with dimethyl fumarate, an NRF2 activator in current use for multiple sclerosis.
Axonal degeneration and locomotor impairment in X‐ALD mouse model are prevented with dimethyl fumarate, indicating its therapeutic potential for X‐ALD patients.
This study reports an aberrant, chronic inhibition of the endogenous antioxidant response driven by NRF2 in adrenoleukodystrophy. Reactivating this pathway in the mouse model with dimethyl fumarate unveils a promising therapeutic option.
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